Behavioral stress is unavoidable in our society. Unfortunately, some individuals do not respond appropriately to stressful situations. A number of those seek relief by using illegal psychostimulants. In many regards, these drugs have very similar effects on the body as acute exposure to behavioral stress. Therefore, it is likely that many of the factors that condition individuals to stress may also be activated by the use of illicit drugs. This proposal is designed to determine the long-term effects and interactions between stress and psychostimulant use. In some conscious Sprague-Dawley rats, cocaine or startle evoke substantial increases in systemic vascular resistance (SVR) and renal sympathetic nerve activity concurrent with reductions in cardiac output (CO). We have designated these animals vascular responders. In contrast, rats we identify to be mixed responders have smaller increases in SVR and, instead, an increase in CO in response to cocaine or startle. Vascular responders are more susceptible to cocaine induced cardiomyopathies and hypertension compared to mixed responders. Our data suggest that the primary difference between these groups is that vascular responders have greater CNS-mediated sympathoexcitation in response to stress or psychostimulants. We propose to study the effects of chronic behavioral stress, using the resident-intruder paradigm, or chronic psychostimulants, using cocaine, on acute responses to startle and to cocaine. We hypothesize that repeated exposure to stress or psychostimulants will initially enhance then attenuate autonomic and hypothalamic-pituitary axis (HPA) responsiveness to acute stress or psychostimulants to a greater extent in vascular responders than mixed responders. Moreover, we propose that the differences in responsiveness will be reflected in changes in hypothalamic and limbic neuropeptide receptor or peptide expression and cardiac apoptosis. Finally, we propose that the CNS changes associated with repeated stress will resemble those elicited by repeated psychostimulant administration. We will compare the effects of chronic stress and/or psychostimulants and determine whether there is cross-tolerance regarding the autonomic, neuroendocrine and neurochemical responses to these stimuli. In addition, we have identified two inbred sub-strains of rats that resemble vascular and mixed responders. We propose to study them in a similar manner as the outbred Sprague-Dawley rats. In other words, we propose that greater alterations in neurotransmitter expression will be apparent in the vascular responder sub-strain. These studies will combine the expertise of investigators studying hemodynamic and autonomic responsivity, neuroendocrine indices and central neuronal circuitry to determine the long-term effects of stress or psychostimulant use in models known to be sensitive or resistant to cardiovascular disease. The results will illuminate the similarities and differences in central autonomic and neuroendocrine responsiveness to stress and psychostimulants.